Genetic testing for breast cancer

Susan M. Domchek, MD
Basser Professor of Oncology
University of Pennsylvania
 Risk Factors for Breast Cancer

Sex
Age
Family history
Depends on specific of family history
Depends on whether there is a known genetic susceptibility
Reproductive history
Early first period
Late last period
Postmenopausal estrogen use
Late first child
No breast feeding
ETOH
Obesity
Lack of exercise
 Germline vs Somatic Genetics

Germline the genes you are born with

Can be passed on to relatives
Does not mean that disease will happen
Increased risk of disease
There is no one breast cancer gene

Somatic changes in tumors that are acquired over

time
Can not pass on to relatives
Can be tested as part of decision making for therapy for cancer
 Genetics :Cancer Risk Variants

Single
Common nucleotide
Variants
polymorphisms
Allele Frequency

CHEK2, ATM, NBN BRCA1, BRCA2, TP53

Rare variants (moderate) Rare variants (high)

1 2 5 10
Relative Risk
 Hereditary breast cancer
Predicted
SNP , 14%

Known
SNPs, 14%

Unknown,
50%
Moderate
penetrance ,
4%
Other high
penetrance,
3% BRCA1/2,
15%

Adapted from Couch, Nathanson, & Offit, Science 2014

Germline genetic testing as a paradigm
for individualized care

Risk Assessment
Disease Prevention
Therapeutics

BRCA1/2 as the prototype

BRCA1/2-associated cancers: lifetime risk

Breast cancer: 50%-70%

Second primary breast cancer: 40%-50%

Ovarian cancer: 15-55% BRCA1>BRCA2

Increased risk of other cancers:

Male breast cancer BRCA2>BRCA1
Pancreatic cancer BRCA2
Prostate cancer BRCA2
Melanoma BRCA2
 Who should be considered for testing?

Breast cancer <45

Ovarian cancer cases (particularly high grade serous)
Male Breast Cancer
Breast and ovarian cancer in a single lineage
2 or more women with breast cancer <50
Ashkenazi Jewish with breast or ovarian cancer
Breast cancer < 60 and triple negative
Bilateral breast cancer <60
Pay attention to pancreatic cancer and high grade prostate
cancer
Ashkenazi Jewish individuals?
All women at age 30? Many issues related to population
screening
Estimates of breast cancer risk in BRCA1 carriers:
Significant variability in penetrance

100% Easton, 1995

% Affected with Breast Cancer

all mutations
90% linkage families
80% Penn Clinic
Brose et al JNCI 2002
70%
Streuwing, 1997
60%
185delAG, 5382insC
50%
Hopper, 1999
40% consecutive breast ca
cases
30% Fodor, 1998
185delAG,
20% 5382insC
10% consecutive breast
ca cases
0%
30 40 50 60 70 80 85
AgeAge
 Genetic modifiers: CIMBA

1.0
5%, 95%
10%, 90% Polygenic risk
Average
scores (PRS) using
BRCA1 carriers

BC susceptibility
0.8

SNPs identified
through
population-based
Breast cancer risk

0.6

GWAS

15,252 BRCA1
0.4

8,211 BRCA2
0.2
0.0

30 40 50 60 70 80

Age
Kuchenbaecker et al in press 2016
 Risk Reducing Salpingo-Oophorectomy and the
risk of breast cancer
No Prior Breast Cancer
Total BRCA1 BRCA2
Total Participants 1,370 869 501
HR (95% CI) 0.54 (0.37-0.79) 0.63 (0.41-0.96) 0.36 (0.16-0.82)

RRSO and the risk of ovarian cancer

Breast cancer prior
Total BRCA1 BRCA2
Total Participants 1060 684 376
HR (95% CI) 0.14 (0.04-0.59) 0.15 (0.04-0.63) No cancer events

PROSE Consortium Domchek et al, JAMA 2010

 RRSO and all-cause mortality

All eligible women

All BRCA1 BRCA2

Total Participants 2,482 1587 895

HR (95% CI) 0.40 (0.26-0.61) 0.38 (0.24-0.62) 0.52 (0.22-1.23)

Domchek et al, JAMA 2010

Domchek et al, JAMA 2010

 Treatment of BRCA1/2-associated cancers:
Platinum and PARP inhibitors

Olaparib Poly ADP ribose polymerase (PARP)

Veliparib plays a role in the repair of single strand
Rucaparib breaks through base excision repair
Niraparib
Significant responses observed in
BMN-673 patients with germline BRCA1/2-
associated breast and ovarian cancer

Tutt et al, Lancet 2010

Audeh et al, Lancet 2010
Gelmon et al, Lancet Oncology 2011
Tumor shrinkage

Tutt et al, Lancet 2010

Approval is for germline BRCA1 and BRCA2 associated
ovarian cancer after treatment with >3 lines of therapy

The FDA did not approve maintenance therapy

EMA did approve maintenance
Multiple tumor types
Cisplatin-resistant ovarian cancer
Breast cancer with >3 lines of therapy in metastatic setting
Pancreatic and prostate cancer

Kaufman et al, JCO 2015

Domchek et al, Gyn Onc 2016
 Ovarian Breast Pancreas Prostate Other All
(n=193) (n=62) (n=23) (n=8) (n=12) (n=298)
BRCA status, n (%)
BRCA1 mutation 148 (76.7) 37 (59.7) 5 (21.7) 1 (12.5) 7 (58.3) 198 (66.4)
BRCA2 mutation 44 (22.8) 25 (40.3) 17 (73.9) 7 (87.5) 5 (41.7) 98 (32.9)
Both 1 (0.5) 0 1 (4.3) 0 0 2 (0.7)
Median (SD) prior 4.3 (2.2) 4.6 (2.0) 2.0 (1.6) 2.0 (1.0) 2.2 (1.3) 4.0 (2.2)
regimens for
advanced disease
Tumor response rate 60 (31.1) 8 (12.9) 5 (21.7) 4 (50) 1 (8.3) 78 (26.2)

Complete response 6 (3.1) 0 1 (4.3) 0 0 7 (2.3)

Partial response 54 (28) 8 (12.9) 4 (17) 4 (50) 1 (8.3) 71 (23.8)

Stable (>8wks) 78 (40) 29 (47) 8 (35) 2 (25) 7 (58) 124 (42)

Stable disease 64 (33) 22 (36) 5 (22) 2 (25) 6 (50) 99 (33)
Unconfirmed PR 12 (6) 7 (11) 3 (13) 0 1 (8.3) 25 (9)

Kaufman et al JCO, 2015

 Platinum resistance and PARP treatment
Platinum sensitivity Confirmed ORR, Median DoR,
status responders % months
Data from the gyn onc paper
(N= with measurable n (95% CI) (95% CI)
disease)
Total (N = 137) 46 34 (2642) 7.9 (5.69.6)

Platinum sensitive
(N = 39) 18 46 (3063) 8.2 (5.613.5)

Platinum resistant
(N = 81) 24 30 (2041) 8.0 (4.814.8)

Platinum refractory
(N = 14) 2 14 (243) 6.4 (5.47.4)

Platinum status
unknown (N = 3) 2 67 (999) 6.3 (4.77.9)

Domchek et al, Gyn Onc 2016

Genetic testing has become complicated.

Single nucleotide polymorphism panels

 Key Points

Not comprehensive sequencing of genes such as BRCA1/2

Not a stand alone for those with a strong family history
Some change in reclassification (change in how you
consider someone from a risk perspective)
Calibration: How closely the predicted probabilities agree
with the actual outcome
Clinical utility (or actionability?)
Will more women take tamoxifen?
How should this impact screening in the era of changing screening
recommendations?

Ongoing studies
In the US - this has become very complicated.
 Ambry Ambry Ambry
Myriad Uwash Fulgent Myriad Uwash Fulgent Fulgent
Gene Cancer Invitae GeneDx Gene Cancer Invitae GeneDx Gene Renal or
MyRisk BROCA * MyRisk BROCA * *
Next Next PGL
# of genes 25 28 28 30 50 110 BARD1 x x x x x FH x x
APC x x x x x x RAD51D x x x x x FLCN x x
ATM x x x x x x MRE11A x x x MAX x x
BMPR1A x x x x x x RAD50 x x x MET x x
BRCA1 x x x x x x NF1 x x MITF x x
BRCA2 x x x x x x VHL Renal/PGL x x x x SDHA x x
BRIP1 x x x x x x MEN1 x x x SDHAF2 x x
CDH1 x x x x x x RET PGL x x x TMEM127 x x
CDK4 x x x x x x PTCH1 x x TSC1 x x
CDKN2A x x x x x x PALLD x TSC2 x x
CHEK2 x x x x x x XRCC2 x x x
EPCAM x x x x x x CHEK1 x x *Rest of genes on Fulgent:
MLH1 x x x x x x AXIN2 x x BLM, BUB1B, CTNNB1,
MSH2 x x x x x x FANCC x x CYLD, DDB2, DICER1, EGFR,
ATR x x EGLN1, ERCC2, ERCC3,
MSH6 x x x x x x
ERCC4, ERCC5, EXO1, EXT1,
MUTYH x x x x x x BAP1 x x
EXT2, FANCA, FANCB,
NBN x x x x x x GALNT12 x x FANCD2, FANCE, FANCF,
PALB2 x x x x x x HOXB13 x x FANCG, FANCI, FANCL,
PMS2 x x x x x x POLD1 x x FANCM, GPC3, HRAS,
PTEN x x x x x x PRSS1 x x KIF1B, KIT, MC1R, MPL,
RAD51A x x MSH3, NF2, PDGFRA,
RAD51C x x x x x x
SDHB x x PICALM, PMS1, PRKAR1A,
SMAD4 x x x x x x Renal/PGL
PRKDC, PTPN11, RB1,
STK11 x x x x x x SDHC Renal/PGL x x
RBBP8, RBM15, RECQL4,
TP53 x x x x x x SDHD Renal/PGL x x ROBO2, SBDS, SLX4,
AKT1 x SMARCB1, SUFU, TERT,
CTNNA1 x TSHR, TYR, WRN ,WT1,
FAM175A x XPA, XPC, XRCC3
GEN1 x
GREM1 x
PIK3CA x
POLE x
PPM1D x
TP53BP1 x
 Revolution of genetic testing

Assess
patient

Test for Test for

most likely most likely
gene(s) gene(s)

Disclose
result and
reassess
New approach?

Assess
patient

Send
multigene
panel

Disclose
result and
reassess
 Why do this?

More cost effective (for the testing) to do multigene

rather than serial testing
Patients (and providers!) can get testing fatigue
The same cancer can be seen with different genes
mutations
Ovarian cancer in both BRCA1/2 and Lynch
Uterine cancer in Lynch and Cowden
Breast in Li-Fraumeni and BRCA1/2
Isnt more better?
 Potential Issues

High penetrance and moderate penetrance genes

are on one panel
Implications for counseling
Keeping track of it all
Dont we recognize clinical syndromes?
(And if we dont what does it mean?)

Variants of uncertain significance

Clinical utility: order tests you will act on

At least actionability
Domchek et al, JCO 2013
 What will we find?
BRCA1/2 negative patients with BC <40
N=278

Patients with Class 4 VUS Class 3 VUS(s) MUTYH No Class 3-5

& Class 5 Mutations only Heterozygotes Variants
N=31 (11%) N=49 (18%) N=6 (2.2%)* N=192 (69%)

Bin A Genes Bin B Genes

TP53, PTEN, STK11, CDH1, ATM, BARD1, BRIP1, CHEK2, 13% 6%

CDKN2A, MLH1, MSH2, FAM175A, MRE11A, NBN, 13% 31%

MSH6, PMS2, MUTYH (AR) PALB2, RAD50, RAD51C 74% 63%
Risk established for breast Risk established for breast White Non-white
or other cancers and some other cancers
Guidelines available Less clear actionability
*Clinically actionable* N=24 (8.6%)
N=7 (2.5%)

Class 4/5 Mutation Class 3 VUS

No Class 3-5 Variants
TP53 MSH2 CDKN2A MUTYH ATM & CHEK2 Other genes
N=4 N=1 N=1 N=1 N=18 N=6

Maxwell et al GIM, 2014

 What do we do? ACCE Framework
Parameter Definition
Analytic How well test measures property or
validity characteristic it is intended to measure
Accuracy of the test in diagnosing or
Clinical
predicting risk for the health condition
validity
(sensitivity, specificity, PPV, NPV)
Evidence of improved measurable clinical
outcomes
Clinical Utility
Usefulness and added value to patient
management

ELSI Ethical, legal and social implications

 What is actionable?

Something that potentially could be acted upon

It does not mean that it is acted upon

It does not mean that such action benefits a patient

Actionability = clinical utility

Critically important that all this be studied
 Summary of Clinical Validity
Gene Breast Ovary Other
ATM Y N ?Pancreas
CHEK2 Y N ?Colon
PALB2 Y N ?Pancreas
NBN Y (657del5) N
BRIP1 N Y
RAD51C/D N Y
RAD51B N ?
BARD1 N N
MRE11A/RAD50 N N

Easton et al, NEJM 2015

 Clinical utility

Risk assessment
Value of the true negative
Risk of breast and as well as risk of second primary
cancer
Risk of other cancers (Ovarian cancer risk for
BRCA1/2 was a major reason for rapid uptake of
testing)
 Clinical utility

Screening and prevention

Need to understand risks and benefits
What age to start screening?
What screening?
What age to have preventative surgery?
What to do with unexpected high penetrance mutation
When we find things we dont expect, what should we do?
 Clinical utility

Therapeutics
Prognosis: may impact administration of adjuvant
therapy

Drug development/selection

Will tumors with mutations in these other genes be

sensitive to specific types of drugs?
 Conclusions

Genetic testing can be very useful to patients and their family members
Both the prevent and to treat cancer
Genetic testing is continuously evolving

BRCA1 and BRCA2 mutations are the most commonly found and we
have reasonable data on how to manage

New genetics tests are often less clear in terms of how to change
patients care and improve patient outcome

Variants of unknown significance should NOT be managed as

mutations

In the face of rising prophylactic mastectomies, we need to emphasize

to patients how mutations in these genes are different from those in
BRCA1/2